Compositions of phosphorylated tau peptides and uses thereof
Inventors
Ramsburg, Elizabeth Anne • De Marco, Donata • Sadaka, Charlotte • Goudsmit, Jaap • Muhs, Andreas • Pihlgren Bosch, Maria • Vukicevic Verhille, Marija • Hickman, David • Piot, Nicolas • Ghimire, Saroj Raj
Assignees
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Publication Number
US-11958889-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Liposomes containing tau peptides, preferably phosphorylated tau peptides, and conjugates containing tau peptides, preferably phosphorylated tau peptides, conjugated to an immunogenic carrier are described. Pharmaceutical compositions and uses of the liposomes and/or conjugates for treating or preventing a neurodegenerative disease or disorder, such as Alzheimer's Disease, are also described.
Core Innovation
The invention relates to tau peptide-based immunogenic compositions for tauopathy, including neurodegenerative disease such as Alzheimer’s disease. The compositions include liposomes that present tau peptides on the surface, with tau peptides having amino acid sequences selected from SEQ ID NOs: 2, 5, 9, and 12, or specifically SEQ ID NO: 2 or SEQ ID NO: 28. The tau presented on the liposome surface is associated with pathological tau structures such as neurofibrillary lesions, ePHF, paired helical filaments (PHF), and tangles.
The liposomes also include a helper T cell epitope comprising at least one amino acid sequence selected from specified SEQ ID NO sets, together with a lipidated CpG oligonucleotide that includes CpG motifs with phosphorothioate internucleotide linkages and is covalently linked to at least one cholesterol via a linker. In addition, the liposomes include monophosphoryl lipid A (MPLA), and the liposome further includes lipids selected from DMPC, DMPG, and cholesterol.
The compositions further include pharmaceutical compositions with a pharmaceutically acceptable carrier and are described for induction, treatment, and prevention via priming and boosting immunization. The document indicates that immune responses and antibody titers are evaluated, including antibody titers in rhesus macaques and immunostaining in human brain sections.
Claims Coverage
Independent claims include liposome composition claims that define combinations of a tau peptide presented on the liposome surface, a helper T cell epitope, a lipidated CpG oligonucleotide covalently linked to cholesterol via a linker, and monophosphoryl lipid A (MPLA). Dependent claims further refine allowable sequence selections and optional lipids, and include pharmaceutical composition and immune-response induction by administration for neurodegenerative disorders associated with neurofibrillary lesion formation.
Tau peptide surface presentation with defined sequences
A liposome comprising a tau peptide having an amino acid sequence selected from SEQ ID NOs: 2, 5, 9, and 12, wherein the tau peptide is presented on the surface of the liposome, alternatively comprising SEQ ID NO: 2 or SEQ ID NO: 28.
Helper T cell epitope combined with tau
A liposome comprising a helper T cell epitope comprising at least one amino acid sequence selected from specified SEQ ID NO sets, including SEQ ID NOs: 23, 24, 25, and 26, or SEQ ID NOs: 39, 40, 41, 42, and 43, or SEQ ID NOs: 13, 14, or 15.
Lipidated CpG oligonucleotide covalently linked to cholesterol
A liposome comprising a lipidated CpG oligonucleotide, wherein the CpG oligonucleotide comprises one or more phosphorothioate internucleotide linkages, and wherein the CpG oligonucleotide is covalently linked to at least one cholesterol via a linker, alternatively having a nucleotide sequence selected from SEQ ID NO: 18 to SEQ ID NO: 22, or SEQ ID NO: 18.
Monophosphoryl lipid A included in the liposome
Monophosphoryl lipid A (MPLA) is included in the liposome composition.
Optional additional lipids
The liposome further includes lipids selected from DMPC, DMPG, and cholesterol.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition including the liposome together with a pharmaceutically acceptable carrier.
Administration to induce an immune response for neurofibrillary lesions
A method for inducing an immune response in a subject with a neurodegenerative disorder associated with neurofibrillary lesion formation by administering the pharmaceutical composition.
Across the claims, the inventive core is a liposome that co-presents a tau peptide on the surface with a helper T cell epitope and includes a lipidated CpG oligonucleotide covalently linked to cholesterol via a linker, together with monophosphoryl lipid A (MPLA). Dependent coverage adds specific SEQ ID NO selections, optional additional lipids, and extends to pharmaceutical compositions and methods for administering the composition to induce immune responses in neurodegenerative disorders associated with neurofibrillary lesion formation.
Stated Advantages
Inducing an immune response in a subject with a neurodegenerative disorder associated with neurofibrillary lesion formation.
Documented Applications
Inducing an immune response in a subject with a neurodegenerative disorder associated with neurofibrillary lesion formation by administering the pharmaceutical composition.
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